Genomic Amplification of <i>TBC1D31</i> Promotes Hepatocellular Carcinoma Through Reducing the Rab22A‐Mediated Endolysosomal Trafficking and Degradation of EGFR
Hepatocellular carcinomas (HCCs) are characterized by a vast spectrum of somatic copy number alterations (CNAs); however, their functional relevance is largely unknown. By performing a genome-wide survey on prognosis-associated focal CNAs in 814 HCC patients by an integrative computational framework based on transcriptomic data, genomic amplification is identified at 8q24.13 as a promising candidate. Further evidence is provided that the 8q24.13 amplification-driven overexpression of Rab GTPase activating protein TBC1D31 exacerbates HCC growth and metastasis both in vitro and in vivo through activating Epidermal growth factor receptor (EGFR) signaling. Mechanistically, TBC1D31 acts as a Rab GTPase activating protein to catalyze GTP hydrolysis for Rab22A and then reduces the Rab22A-mediated endolysosomal trafficking and degradation of EGFR. Notably, overexpression of TBC1D31 markedly increases the resistance of HCC cells to lenvatinib, whereas inhibition of the TBC1D31-EGFR axis can reverse this resistance phenotype. This study highlights that TBC1D31 at 8q24.13 is a new critical oncogene, uncovers a novel mechanism of EGFR activation in HCC, and proposes the potential strategies for treating HCC patients with TBC1D31 amplification or overexpression.
Authors
- Anfeng Si
- Hongxia Chen
- Chengming Gao
- Qingfeng Song (ORCID: https://orcid.org/0000-0003-4314-6897)
- Chenning Yang
- Pengbo Cao (ORCID: https://orcid.org/0000-0002-7820-114X)
- Bingqian Guo (ORCID: https://orcid.org/0000-0003-1503-111X)
- Gangqiao Zhou (ORCID: https://orcid.org/0000-0002-4895-5063)
- Yuanfeng Li (ORCID: https://orcid.org/0000-0001-8227-7019)
- Aiqing Yang (ORCID: https://orcid.org/0000-0002-8825-099X)
- Hua Li (ORCID: https://orcid.org/0000-0003-1903-836X)
- Qi Zhang (ORCID: https://orcid.org/0000-0001-9916-8919)
- Xinyi Liu (ORCID: https://orcid.org/0000-0001-5983-2766)
- Xiaowen Wang (ORCID: https://orcid.org/0000-0002-7248-955X)
- Yahui Wang (ORCID: https://orcid.org/0000-0001-6645-8485)
- Ying Zhang (ORCID: https://orcid.org/0000-0003-1537-4526)
- Fuchu He
- Huihui Han (ORCID: https://orcid.org/0009-0001-0269-8321)
- Mengting Shi
- Liang Jin (ORCID: https://orcid.org/0000-0002-1954-4345)
- Rongjiao Hao
- Xi Zhao
Institutions
- Guangxi Medical University (CN)
- Nanjing General Hospital of Nanjing Military Command (CN)
- Chengdu Military General Hospital (CN)
- Beijing Proteome Research Center (CN)
- Hebei University (CN)
- Nanjing University (CN)
- University of South China (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1002/advs.202405459
- Citations
- 4
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China